"Slow Reacting Substance of Anaphylaxis" (SRS-A) has been shown to be a highly potent bronchoconstricting substance which is released primarily from mast cells and basophils on antigenic challenge. SRS-A has been proposed as a primary mediator in human asthma. SRS-A, in addition to its pronounced effects on lung tissue, also produces permeability changes in skin and may be involved in acute cutaneous allergic reactions. Further, SRS-A has been shown to effect depression of ventricular contraction and potentiation of the cardiovascular effects of histamine.
Leukotrienenes are a group of eicosanoids formed from arachidonic acid metabolism via the lipoxygenase pathway. These lipid derivatives originate from LTA.sub.4 and are of two types: (1) those containing a sulfidopeptide side chain (LTC.sub.4, LTD.sub.4, and LTE.sub.4), and (2) those that are nonpeptidic (LTB.sub.4). Leukotrienes comprise a group of naturally occuring substances that have the potential to contribute significantly to the pathogensis of a variety of inflammatory and ischemic disorders.
As summarized by Lefer, A. M., Biochemical Pharmacology, 35, 2, 123-127 (1986) both the peptide and non-peptide leukotrienes exert microcirculatory actions, promoting leakage of fluid across the capillary endothelial membrane in most types of vascular beds. LTB.sub.4 has potent chemotatic actions and contributes to the recruitment and adherence of mobile scavenger cells to endothelial membrane. LTC.sub.4, LTD.sub.4 and LTE.sub.4 stimulate a variety of types of muscles. LTC.sub.4 and LTD.sub.4 are potent bronchoconstrictors and effective stimulators of vascular smooth muscle. This vasoconstrictor effect has been shown to occur in pulmonary, coronary, cerebral, renal, and mesenteric vasculatures.
Leukotrienes have been implicated in a number of pulmonary diseases. Leukotrienes are known to be potent bronchoconstrictors in humans. LTC.sub.4 and LTD.sub.4 have been shown to be potent and selective peripheral airway agonists, being more active than histamine. [See Drazen, J. M. et al., Proc. Nat'l, Acad. Sci. U.S.A., 77, 7, 4354-4358 (1980)]. LTC.sub.4 and LTD.sub.4 have been shown to increase the release of mucous from human airways in vitro. [See Marom, Z. et al., Am. Rev. Respir. Dis., 126, 449-451 (1982).] The leukotriene antagonists of the present invention can be useful in the treatment of allergic or non-allergic bronchial asthma or plumonary anaphylaxis.
Leukotrienes have been identified in the nasal secretions of allergic subjects who underwent in vivo challenge with specific antigen. The release of the leukotrienes was correlated with typical allergic signs and symptoms. [See Creticos, P. S. et al., New England J. of Med., 310, 25, 1626-1629 (1984). This suggests that allergic rhinitis is another area of utility for leukotriene antagonists.
Leukotrienes have also been directly or indirectly implicated in a variety of non-pulmonary diseases in the ocular, dermatologic, cardiovascular, renal, trauma, inflammatory, carcinogenic and other areas.
Leukotriene antagonists can also be useful in the area of renal ischemia or renal failure. Badr et al. have shown that LTC.sub.4 produces significant elevation of mean arterial pressure and reductions in cardiac output and renal blood flow, and that such effects can be abolished by a specific leukotriene antagonist. [See Badr, K. F. et al., Circulation Research, 54, 5, 492-499 (1984). Leukotrienes have also been shown to have a role in endotoxin enduced renal failure and the effects of the leukotrienes selectively antagonized in this model of renal injury. [See Badr, K. F. et al., Kideny International, 30, 474-480 (1986).] LTD.sub.4 has been shown to produce local glomerular constrictor actions which are prevented by treatment with a leukotriene antagonist, [See Badr, K. F. et al., Kidney International, 29, 1, 328 (1986). LTC.sub.4 has been demonstrated to contract rat glomerular mesangial cells in culture and thereby effect intraglomerular actions to reduce filtration surface area. [See Dunn, M. J. et al., Kidney International, 27, 1, 256 (1985). Thus another area of utility for leukotriene antagonists can be in the treatment of glomerulonephritis.
Cysteinyl leukotrienes have also been shown to undergo enterohepatic circulation, and thus are indicated in the area of inflammatory liver disease. [See Denzlinger, C. et al., Prostaglandins Leukotrienes and Medicine, 21, 321-322 (1986). Leukotrienes can also be important mediators of inflammation in inflammatory bowel disease. [See Peskar, B. M. et al., Agents and Actions, 18, 381-383 (1986).] Leukotriene antagonists thus can be useful in the treatment of inflammatory liver and bowel disease.
By antagonizing the effects of LTC.sub.4, LTD.sub.4 and LTE.sub.4 or other pharmacologically active mediators at the end organ, for example airway smooth muscle, the compounds and pharmaceutical compositions of the instant invention are valuable in the treatment of diseases in subjects, including human or animals, in which leukotrienes are a key factor.
Leukotriene antagonists based on 3-phenyl-3-carboxyalkylthioalkanoic acids are disclosed in U.S. Pat. No. 4,820,719.